DESCRIPTION
Ephedrine is a sympathomimetic amine commonly used as a stimulant, appetite suppressant, concentration aid, decongestant, and to treat hypotension associated with anaesthesia.
Ephedrine is obtained from several species of the Ephedra genus. In particular the herb má huáng (麻黄, Ephedra sinica), used in traditional Chinese medicine, contains ephedrine and pseudoephedrine as its principal active constituents and its use has been documented in China since the second century BC as an antiasthmatic and stimulant.
CLASSIFICATION
Ephedrine is a substituted amphetamine and a structural methamphetamine analogue. It differs from methamphetamine only by the presence of a hydroxyl (OH). Amphetamines, however, are more potent and have additional biological effects.
Ephedrine is also similar in molecular structure to the well-known drug phenylpropanolamine as well as to the neurotransmitter norepinephrine (noradrenalin). It works mainly by increasing the activity of norepinephrine (noradrenalin) on adrenergic receptors.
Ephedrine exhibits optical isomerism and has two chiral centres, giving rise to four stereoisomers.
INDICATIONS
- Ephedrine increases blood pressure and acts as bronchodilator.
- It may be used treat spinal/epidural anesthesia related hypotension.
- It promotes weight loss, specifically fat loss in humans and mice. In mice ephedrine is known to stimulate thermogenesis in the brown adipose tissue. Methylxanthines like caffeine and theophylline have a synergistic effect with ephedrine with respect to weight loss, and so does aspirin.
- Ephedrine also decreases gastric emptying.
- For many years, the US Coast Guard recommended the so-called Coast Guard cocktail (ephedrine together with an equal 25 mg dose of promethazine) to its sailors to combat seasickness. Promethazine manages nausea and ephedrine fights the ensuing drowsiness.
- It acts as a vasoconstrictor in the treatment of haemorragic shock (Ephedrine in the initial treatment of haemorrhagic shock. 1991)
PHARMACOKINETICS
Ephedrine may have different routes of administration: oral, subcutaneous, intramuscular and intravenous.
Small amounts are slowly metabolized in the liver and it is renally eliminated mostly as unchanged drug. The t ½ is approximately 3 to 6 h (dependent on urinary pH). Onset and duration depend on the route of administration.
Ephedrine is excreted in breast milk.
MOLECULAR MECHANISM
Ephedrine is a sympathomimetic amine. L-Ephedrine has indirect sympathomimetic effects and due to its ability to cross the blood brain barrier, it also releases noradrenaline and dopamine in substantia nigra thus being a CNS stimulant similar to amphetamines but less pronounced. The principal mechanism of its action however relies on its indirect stimulation of the adrenergic receptor system, which is part of the sympathetic nervous system (SNS).
Ephedrine increases post-synaptic noradrenergic receptor activity by (weakly) directly activating post-synaptic α-receptors and β-receptors. The hypothesis of direct interactions with α-receptors is still controversial.
The stimulation of β-receptors leads to:
- smooth muscle relaxation, hence ephedrine's bronchodilatative action;
- positive inotropic, chronotropic and dromotropic action, explaining ephedrine's use to treat hypotension;
- variation of glucose methabolism (inibition of insulin release, stimulation of gluconeogenesis and glucolysis) and enhanced lipolysis, hence ephedrine's use to promote weight loss.
The presence of an N-methyl group in ephedrine decreases its binding affinity at α-receptors compared with norephedrine (also known as phenylpropanolamine), but ephedrine binds better than N-methylephedrine, which has an ulterior methyl group.
Norephedrine (also known as phenylpropanolamine)
Ephedrine
N-Methylephedrine
It is important to underline that the bulk of ephedrine’s effect comes from the pre-synaptic neuron being unable to distinguish between real noradrenaline from ephedrine. Ephedrine, along with noradrenaline, is transported through the noradrenaline reuptake complex and packaged into vesicles that reside at the terminal button of a nerve cell. Ephedrine's action as an agonist at most major noradrenaline receptors and its ability to increase the release of both dopamine and, to a lesser extent, serotonin by the same mechanism is presumed to have a major role in its mechanism of action.
SIDE EFFECTS
Adverse drug reactions are more common with systemic administration (e.g. injection or oral administration) compared to topical administration (e.g. nasal instillations). ADRs associated with ephedrine therapy include:
- Cardiovascular: tachycardia, arrhythmias, angina pectoris, vasoconstriction with hypertension.
- Dermatological: flushing, sweating, acne.
- Gastrointestinal: nausea.
- Genitourinary: decreased urination due to vasoconstriction of renal arteries. Also, difficulty urinating is not uncommon, as alpha-agonists such as ephedrine constrict the internal urethral sphincter, mimicking the effects of sympathetic nervous system stimulation.
- Nervous system: restlessness and agitation, confusion, insomnia, mild euphoria, mania/hallucinations (rare except in previously existing psychiatric conditions), delusions, paranoia, hostility, panic.
- Respiratory: dyspnea, pulmonary edema.
- Miscellaneous: dizziness, headache, tremor, hyperglycemic reactions, dry mouth.
TOXICITY
Ephedrine combined with caffeine is cardiotoxic and, because of this, dietary supplements including the two substances used for weight loss and athletic performance enhancement are now illegal in many countries. Studies performed on rats have associated this kind of compounds and dietary supplements with:
Regular use of compounds associating ephedrine and caffeine increases post-prandial glucose and insulin and produces a rise in insulin resistance and hypokaliemia in healthy subjects (Ephedra and caffeine produce insulin resistance and hypokalemia in healthy subjects. 2004).
Ephedrine should not be used at any time during pregnancy unless specifically indicated by a qualified physician and only when other options are unavailable.
The neurotoxicity of ephedrine is disputed.
ILLICIT USE AND LEGALITY
- Ephedrine has been combined with caffeine and aspirin in a compound product known as the ECA stack (ECA is an acronym for its three principal constituents) which was popularly used in weight loss, body building and as a stimulant. Due to deaths linked to ephedra-containing dietary supplements and the potential use of ephedrine as a precursor in illegal methamphetamine manufacture, many countries have taken steps to regulate this product.
- Anecdotal reports have suggested that ephedrine helps studying, thinking, or concentrating to a greater extent than caffeine. Some students and some white-collar workers have used ephedrine (or Ephedra-containing herbal supplements such as Ephedra tea) for this purpose, as well as some professional athletes and weightlifters. Such use of ephedrine has been associated with stimulant dependence.
- As a phenylethylamine, ephedrine has a similar chemical structure to amphetamines and is a methamphetamine analogue. Because of ephedrine's structural similarity to methamphetamine it can be used to create methamphetamine using chemical reduction in which ephedrine's hydroxyl group is removed; this has made ephedrine a highly sought-after chemical precursor in the illicit manufacture of methamphetamine.
- In E for Ecstasy (a book examining the uses of the drug in the UK) the writer Nicholas Saunders highlighted test results showing that certain consignments of the drug also contained ephedrine.
